1. Field of the Invention
The present invention relates generally to the fields of blood vessels and to radiation biology. More particularly, it provides a variety of compositions and methods for use in targeting the E-selectin or L-selectin marker following its specific induction in tumor vasculature endothelial cells, and for delivering selected therapeutic and diagnostic agents to the tumor vasculature.
2. Description of the Related Art
Although significant effort continues to be applied to the development of effective anti-cancer strategies, many prevalent forms of human cancer still resist effective chemotherapeutic intervention. A considerable underlying problem that must be addressed in any treatment regimen is the concept of "total cell kill." This is based on the fact that in order to have an effective treatment regimen, whether it be a surgical or chemotherapeutic approach, or both, all of the so-called "clonogenic" malignant cells must be killed to prevent regrowth of the tumor mass.
Due to the need to develop therapeutic agents and regimens capable of achieving such total cell kill, certain types of tumors have been more amenable than others to therapy. For example, lymphomas, and tumors of the blood and blood-forming organs, e.g., leukemias, have generally been more responsive to chemotherapeutic therapy, while solid tumors, such as carcinomas, generally prove more resistant to such therapies.
One underlying reason for this phenomenon is that blood-based tumors are physically more accessible to the chemotherapeutic agents, whereas it is often difficult for most chemotherapeutic agents to reach all of the cells of a solid tumor. Increasing the dose of chemotherapeutic agents, rather than achieving the desired total cell kill, most often results in toxic side effects that limit the effectiveness the chemotherapy.
Even immunotoxins, that are directed to selected cancer cell antigens, have proven to be of limited use in the treatment of solid tumors (Weiner et al., 1989; Byers et al., 1989). One reason for this is that solid tumors are generally impermeable to antibody-sized molecules, often exhibiting specific uptake values of less than 0.001% of the injected dose/g of tumor in human studies (Sands et al., 1988; Epenetos et al., 1986).
Further significant problems that can apply to any conventional chemotherapeutic include: the formation of mutants that escape cell killing and regrow; the dense packing of cells within the tumor that creates a physical barrier to macromolecular transport; the absence of lymphatic drainage, creating an elevated interstitial pressure that reduces extravasation and fluid convection; the heterogeneous distribution of blood vessels that leaves certain tumor cells at a considerable diffusion distance; and the adsorption of agents in the perivascular tumor cells.
It is therefore clear that a significant need exists for the development of novel strategies for the treatment of solid tumors. One approach involves the targeting of agents to the vasculature of the tumor, rather than to tumor cells. As solid tumor growth is dependent on the vascularization of the tumor to supply oxygen, nutrients and other growth factors, vascular-mediated mechanisms of action appear attractive. Also, in targeting the vasculature, the cells are generally accessible and the outgrowth of mutant endothelial cells, lacking a target antigen, is unlikely because they are normal cells.
For tumor vascular targeting to succeed, it is generally accepted that markers must be identified that are specific for tumor vascular endothelial cells and that are not significantly expressed in such cells in normal tissues. The failure to identify or develop appropriately effective markers has generally limited the development of the initially promising anti-vascular strategies.